Biochem Biophys Res Commun 2025 Sep 15;784:152656. doi: 10.1016/j.bbrc.2025.152656.

Mtx2 requirement for craniofacial morphogenesis with implications for mandibuloacral dysplasia.

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Mtx2 is a mitochondrial outer membrane protein with conserved GST-like domains, previously implicated in mitochondrial protein import and apoptosis regulation. Mutations in MTX2 are associated with mandibuloacral dysplasia (MADaM), a congenital disorder characterized by craniofacial anomalies; however, its developmental role remains poorly understood. Here, we demonstrate that Mtx2 is essential for craniofacial development in Xenopus laevis. Knockdown of mtx2 led to reduced head size and hypoplastic cranial cartilage, along with disrupted expression of neural crest and chondrogenic markers. These defects were accompanied by decreased cell proliferation and increased apoptosis. To define the domain-specific requirements of Mtx2, we performed deletion-rescue experiments. Deletion of the N-terminal GST-like domain permitted phenotypic rescue, whereas deletion of the C-terminal domain failed to restore craniofacial morphology or cartilage formation. Our findings reveal a novel developmental role for Mtx2 and establish its C-terminal GST-like domain as essential for craniofacial morphogenesis, providing mechanistic insight into how Mtx2 dysfunction may contribute to craniofacial defects observed in MADaM.

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